Craniofacial anomalies in general in clefts of the lip and/or palate in particular are common human birth defects. These abnormalities require significant surgical, dental, speech, and behavioral interventions and impose substantial economic and societal burdens. More than 400 syndromes, chromosomal abnormalities and teratogenic exposures are known to result in clefts. These occur secondary to a complex interplay of gene-gene and gene environmental interactions which underly the wide variation in phenotype seen in these disorders. Although the causes of craniofacial anomalies including clefts have been investigated intensively, it has only been in the last few years that successful gene identification has begun and now offers the promise of improvements in diagnosis, treatment, and prevention. The successes have been the result of collaborative interactions between clinicians and scientists expert in animal models, phenotyping, statistical/quantitative analysis and gene-finding. In our Craniofacial Anomalies Research Center we will build on an over forty year history at the University of Iowa in investigations into these disorders. We have assembled an international team with substantial experience and expertise who will closely interact through five primary projects and five support cores to perform an integrated set of investigations aimed at improving our understanding of cleft lip and palate. Mouse model studies will complement those of human gene finding and all investigations will benefit from genomic approaches in characterizing genes and gene expression. The outcome of this project will be immediate and direct contributions to a better understanding of the genetic aspects of clefting in both humans and animal models and far better insights into the basic biology of craniofacial development. It will confirm proof of principle that complex human craniofacial disorders can be understood and diagnosis and prevention improved.